Median Number Of Courses Research Articles

A phase II trial of combination chemotherapy with irinotecan and amrubicin in pretreated patients with non-small cell lung cancer

18111 Background: Amrubicin, a totally synthetic anthracycline, is a topoisomerase II inhibitor and highly effective for non-small cell lung cancer (NSCLC) as a single agent with response rates of 25% to 28%. We previously conducted a phase I trial of combination chemotherapy with irinotecan and amrubicin for NSCLC and found acceptable toxicity profiles with a favorable efficacy in patients with pretreated NSCLC. The aim of this phase II trial was to further evaluate its efficacy and toxicity in this population. Methods: Primary endpoint was objective response. Patients with NSCLC previously treated with one or two chemotherapy regimens were enrolled in this trial. Irinotecan and amrubicin were both administered on days 1 and 8, every 3 weeks at doses of 100 and 40 mg/m2, respectively. Response and toxicity were assessed according to the RECIST guideline and NCI Common Terminology Criteria for Adverse Events v3.0. Results: Thirty-one pretreated NSCLC patients were enrolled between 2004 and 2006. A median number of courses administered was 3 (range: 1 to 6). All patients and courses were assessable for efficacy and safety. Demographics of the patients were as follows: M/F: 21/10, Ad/others: 21/10, ECOG-PS 0/1: 12/19, and smoker/non-smoker: 21/10. Platinum-based regimens were commonly used as the prior chemotherapy. Objective response was obtained in 9 of the 31 patients with a response rate of 29.0% (95%CI: 12.1–46.0%). Grade 4 leukopenia and neutropenia were observed in 6 (19%) and 14 (45%) patients, respectively, whereas thrombocytopenia were generally mild. Grade 3 febrile neutropenia was observed in 7 patients (23%), of whom two patients further developed Grade 4 and 5 septic shock each. Other grade 3 or greater non-hematological toxicities included diarrhea, vomiting, pneumonitis, liver dysfunction in 4, 1, 1 and 2 patients, respectively. At the time of this analysis with a median follow-up time in the surviving patients of 7.5 months, median survival time and median progression-free survival time were 11.9 and 4.0 months, respectively. Conclusion: This combination seemed highly effective for pretreated NSCLC despite the moderate toxicity profiles. Development of efficient patient selection is needed to avoid the serious toxicities. No significant financial relationships to disclose.

Cardiotoxicity of weekly trastuzumab (T) plus epirubicin (E) and paclitaxel (P) for HER2-positive locally advanced (LA) and/or metastatic (M) breast cancer (BC): A feasibility phase II study

11509 Background: The introduction of T for patients (pts) overexpressing HER-2 changed the natural history of BC. The adjunction of T to anthracyclines and taxanes for both LABC and MBC provided a significant incidence of unexpected cardiotoxicity. Given the low cardiac toxicity in our previous experience with weekly ET in unselected MBC pts, a feasibility phase II study aimed to cardiotoxicity was planned. Methods: Pts affected by untreated LABC/MBC overexpressing HER-2 by FISH/CISH amplification or 3-positive Dako- Test, underwent weekly T (4–2 mg/kg/week), day 1, and E (25 mg/m2/week) plus P (80 mg/m2/week), day 2, plus G-CSF support, for 16/24 consecutive weeks in absence of progression or toxicity, in LA/M pts, respectively. Pts with significant cardiac disease/L-FEV<50% were excluded. Primary endpoint was the rate of pts with L-FEV reduction >10% after 12 weeks. An optimal 2-stage Simon design was applied. With a power of 90% at a 5% significance level, assuming a toxicity rate of 30% as unacceptable, and less than 10% as acceptable, an initial group of 15 pts was required; with 11 pts with no toxicity, a second step with further 21 pts (total 36) was planned. Non-cardiac toxicity and activity were evaluated as secondary end-points. Results: From May 2004 to November 2006, 15 pts entered the study. Patient characteristics: median age=47 (range 37–69); LABC/MBC=4/11; positive hormonal receptor 8/7; menopausal pre/post=7/8; PS 0/1=14/1; number of met sites 1/2/3=7/6/2. Median baseline- and post-week-12-L-FEV was 69% (range 64–77) and 65% (range 61–76), respectively. With a median number of courses of 13 (range 8–24), 3 pts had a >10% L-FEV reduction (20%), with an overall median L-FEV reduction of 5.2%. No EKG alteration or specific symptoms were registered. With a 17-months median follow-up, 13 pts were evaluable for response. Eight response (61.5%, 95% CI 9- 87) were documented, with a median response duration of 9 months. No grade 3–4 toxicity were registered, with the exception of severe alopecia. Conclusions: The weekly administration of T plus E and P is extremely tolerable, also with regard to L-FEV reduction. The low L- FEV reduction rate allowed entering the second step of the study. No significant financial relationships to disclose.

Rituximab plus cladribine with or without cyclophosphamide in patients with relapsed or refractory chronic lymphocytic leukemia

The aim of our study was to determine the feasibility, effectiveness and toxicity of combined regimens consisting of rituximab and cladribine (2-CdA) (RC) and RC plus cyclophosphamide (RCC) in the treatment of patients with recurrent or refractory chronic lymphocytic leukemia (CLL). The RC regimen consisted of rituximab given on day 1 and 2-CdA (days 2-6). The RCC protocol included rituximab (day 1), 2-CdA (days 2-4) and cyclophosphamide given on days 2-4. The courses were re-administered at time intervals of 4 weeks or longer if severe myelosuppression occurred. Forty-six patients with CLL entered the study. Eighteen patients were treated with RC and 28 with RCC regimen. The median number of courses administered were three cycles (range 1-6). Three (6.5%) patients (95% CI: 1-14%) achieved a complete response and 31 (67%) patients (95% CI: 50-83%) a partial response. According to the particular regimen, the overall response rate was obtained in 12 (67%) patients treated with RC (95% CI: 45-89%) and in 22 patients (78%) treated with RCC (95% CI: 62-93%). The median progression free survival of responders to RC/RCC regimens was 12 months (range 4-46). Hypersensitivity to rituximab occurred in 16 (33%) patients, mostly during the first infusion of the drug. Grade 3/4 neutropenia was seen in six (13%) patients, grade 3/4 thrombocytopenia in three (9%) patients and grade 3/4 infections were observed in ten (28%) patients. These data indicate that both RC and RCC regimens are feasible in heavily pretreated patients with CLL, showing also distinct therapeutic activity and relatively low toxicity, even in patients previously treated with cladribine-based protocols.

Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia

Hypomethylating agents have activity in myelodysplastic syndrome (MDS) and have received approval for the treatment of both MDS and chronic myelomonocytic leukemia (CMML). The specific efficacy in CMML has not been detailed in a large number of patients. The aim of the study was to evaluate the activity and safety of decitabine in CMML. Nineteen adults with a diagnosis of CMML treated on decitabine studies were analyzed. Decitabine was given at 100 mg/m(2) per course every 4 weeks. The median number of courses given was 9 (range, 1-18). Overall, 11 patients (58%) achieved complete response (CR) and 2 (11%) had hematologic improvement (HI), for an overall response rate of 69% according to the modified International Working Group (IWG) criteria. Median survival was 19 months. Severe (grade 3-4) extramedullary side effects were rare. Decitabine is active in CMML. Studies of combinations of decitabine with topoisomerase I inhibitors or other active anti-CMML agents are indicated.

Liposome-encapsulated doxorubicin citrate in previously treated recurrent/metastatic gynecological malignancies

The aim of this study was to evaluate the safety and efficacy of liposome-encapsulated doxorubicin citrate (LEDC) in patients affected by recurrent/metastatic gynecological malignancies scheduled for palliative chemotherapy. Inclusion criteria were proven recurrent/advanced gynecological neoplasms, measurable/assessable disease, adequate organ function, left ventricular ejection fraction >50% as determined by echocardiography, informed consent. LEDC was administered intravenously over 1 h at the dose of either 75 mg/m(2) or 60 mg/m(2) (every 3 weeks until disease progression or toxicity prohibiting further therapy). From May 2003 to September 2005, 36 patients were enrolled. Primary disease was ovarian, endometrial, and cervical cancers in 15 (42%), 11 (30%), and 10 (28%) patients, respectively. LEDC was employed as third- or fourth-line chemotherapy in 25 (70%) and 11 (30%) patients, respectively. The median number of courses of LEDC received was 3 (range 2-9). Six patients (17%) achieved a partial response to treatment lasting 27 weeks and 10 patients (28%) experienced stable disease lasting 18 weeks. The predominant toxicity was hematological, especially neutropenia. Among patients receiving a dose of 75 mg/m(2), two (11%) suspended therapy for febrile neutropenia, and nine (50%) required a dose reduction of 25%. As a result, the next 18 patients were treated at a reduced dose (60 mg/m(2)) of LEDC. Severe neutropenia (G3-G4) was significantly less common in this group (61% versus 22%; P= 0.04). LEDC has shown antineoplastic activity in previously treated recurrent/metastatic gynecological cancer patients and the toxicity profile could be considered acceptable at a 60 mg/m(2) dosage.

Hemoglobin F Induction Is Frequent during Low-Dose 5-aza-2′-Deoxycytidine Treatment of Older AML/MDS Patients.

Introduction: DNA hypermethylation is a frequent epigenetic mechanism for gene silencing in various malignancies. Clinical trials of low-dose DNA methyltransferase (DNMT) inhibitors, e.g. 5-aza-2′-deoxycytidine (Dacogen®, DAC) in AML and advanced MDS have shown encouraging activity, and both global and gene-specific in vivo demethylation (e. g. of the p15/INK4b tumor supressor gene) have been reported and valid surrogate markers for effective epigenetic therapy are warranted. DNMT inhibitors were also successfully used to upregulate HbF in patients (pts) suffering from hemoglobinopathies. We wished to investigate whether HbF induction also occurs during AML and MDS treatment with low-dose DAC. Using K562 and HEL myeloid leukemia cell lines which can be induced to erythroid differentiation by hemin and to megakaryocytic differentiation by phorbol myristate acetate (PMA), we also analyzed in vitro changes in globin transcription induced by DAC.Results: HbF levels were measured by HPLC in peripheral blood from 36 pts (25 with AML and 11 with MDS, median age 76 years, range 67–84) treated with the identical low-dose DAC schedule (135 mg/m2 i.v. over 72 hours). 10 pts had received hydroxyurea (HU) prior to DAC to control leukocytosis. HbF baseline levels varied from 0.1–9.6% (median 0.6%). 22/36 (61%) including 8 pts with prior HU exposed normal HbF levels (≤1.0%), in 14 pts (39%, 2 pts with prior HU) HbF levels were already increased. 27 pts received two or more courses of DAC. In 20/27 pts (74%), an increase in HbF expression during at least one course of treatment could be detected. In 13/15 pts (87%) with initially normal HbF a median increment of 0.8% (0.1–3.7%) was observed, and 7/12 (58%) with initially elevated HbF levels showed further increase (median increment of 1.8%, range 0.7–3.7%) during treatment. Median number of courses until maximum increment was 2 (1–6). In 6 pts HbF levels decreased, in 1 pt HbF expression was unaltered upon DAC treatment.To investigate mechanisms of this induction, K562 and HEL cells were treated with DAC at non-cytotoxic concentrations, i. e. 100 and 20 nM DAC for 3×24 hrs, respectively. Cells showed striking morphological changes, and by benzidine staining became positive for hemoglobin synthesis. mRNA microarray analyses (HG-U133B gene chip, Affymetrix) revealed significant, strong induction of transcripts for alpha 1-, alpha 2-, A gamma-, epsilon-globin expression in both cell lines, zeta-globin expression was substantially increased in K562 cells, whereas beta- and delta-globin were only expressed at low levels. With PMA treatment only delta-globin expression was increased in both cell lines but other globin transcripts were decreased or unchanged.Conclusions: HbF is upregulated in the majority of AML/MDS patients upon treatment with DAC, and alpha- and gamma-globin gene induction by DAC can be modeled in vitro. DNA methylation analyses will be necessary to show whether HbF upregulation in AML/MDS patients treated with DAC is associated with demethylation of the gamma-globin locus. Measurement of HbF could serve as rapid and reproducible method for in vivo monitoring of demethylating therapy.

Significant Clinical Activity of the Combination of 5-Azacytidine, Valproic Acid and All-Trans Retinoic (ATRA) Acid in Leukemia: Results of a Phase I/II Study.

5-azacitidine (5-AC), and its analogue 5-aza-2′-deoxycitidine (5-DAC), are DNA hypomethylating agents. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI). Hypomethylating agents and HDACI restore ATRA sensitivity in resistant cells. The combination of a hypomethylating agent with an HDACI is antileukemic in vitro. Based on this, and on a prior study of 5-DAC and VPA (Garcia-Manero, Blood, in press), we developed a phase I/II study of the combination of 5-AC, VPA and ATRA. Patients (pts) with high risk MDS (≥10% blasts); relapsed/refractory AML; and pts > 60 years with untreated disease and adequate renal, hepatic functions and performance status were eligible. A fixed-dose of 5-AC was used: 75 mg/m2 sq daily x 7. ATRA dose was: 45 mg/m2 PO daily x 5 starting on day 3 of 5-AC. The phase I followed a classic 3+3 design. The initial dose of VPA was 50 mg/kg PO daily x 7 concomitantly with 5-AC. Cycles were at least 21 days long. The phase II targets a response rate of ≥30% with stopping rules. Cohorts of 10 pts (max 40) are studied. Thirty one pts are evaluable. Median age is 60 years (5–78). All, but 2 pts with MDS, had AML. Median number of prior therapies was 2 (0–5). Twenty six pts (83%) had abnormal cytogenetics. During the phase I, at a VPA dose of 50 mg/kg, 1/6 pts developed grade 3 non-hematological toxicity; at 62.5 mg/kg, 2/7, and at 75 mg/kg, 3/6. The dose limiting toxicity (DLT) was neurotoxicity, confusion and somnolence. The MTD was 50 mg/kg daily x 7. Twelve pts are enrolled in the phase II. Of the 31 evaluable pts, 9 achieved CR (ANC 10 9/L, platelets 100 x 10 9/L, and marrow blasts ≤5%) and 3 a CRp (same criteria as of CR but without complete platelet recovery), overall response (OR)39%. The median number of courses to response was 1 (1–3). Nine responses occurred in 16 untreated pts, OR 56% (Table). Eighteen patients were treated at the MTD with 9 responses (50%). Cytogenetic responses were observed in all responding pts. To assess the hypomethylating effect of 5-AC, the LINE test was used. Median LINE methylation pretreatment was 62.5% (57–67%), declined to 58% by day 7 and returned to baseline by day 0 of next cycle (p<0.001). No significant difference was observed between responders and non responders. Eighteen pts had evidence of histone 3 and 4 acetylation (66%). VPA bound level on day 2 was 146 mcg/ml (95% CI 122–170) in responders and 103 mcg/ml (95% CI 88–118) in non-responders, p< 0.005. Analysis of gene re-expression and cell differentiation are ongoing. In conclusion, the combination of 5-AC, VPA and ATRA is safe. The MTD of VPA is 50mg/kg daily x 7. The DLT is neurotoxicity. The combination has significant clinical activity. An OR of 56% was observed in patients > 60 years with previously untreated AML/MDS. Histone acetylation and transient global hypomethylation are observed. Higher levels of VPA are found in responders. Based on prior CALGB experience (Silverman, ASH 2005), this combination appears to be more active than single agent 5-AC in AML. The study continues to accrue.ResponsesVPA (mg/kg)Number of PatientsCRCRpOR%Courses to responseDuration of response (months)501872501(1–3)2.6(0.5–3.2)62.57101423.73+756113318.1(7–9.2+)Total3193381(1–3)2.9(0.5–9.2+)Untreated AML/MDS>60 years1672561(1–3)2.9 (0.5–9.2+)

Imatinib in Children with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (CP CML): AAML0123 COG Study.

Introduction. Our prior phase 1 study (P9973) established the safety profile and suggested efficacy of imatinib in children with CP CML at doses varying from 260–570 mg/m2. The purpose of this phase 2 study was to define the rates of response in children with previously untreated CP CML.Methods. Patients less than 22 years of age at study entry with newly diagnosed CP CML, with no prior therapy other than hydroxyurea, were eligible. Imatinib was administered orally at a dose of 340 mg/m2 daily, with courses defined as 28-day intervals. A hematological response (HR) was defined at the end of courses 1 and 2 as a reduction in the white-cell count to <10 x 109/L and in platelet count to <450 x 109/L, and was considered a complete response (CHR) when maintained for at least four weeks. Cytogenetic response is defined as follows, based on the absolute percent of Ph+ metaphase cells on marrow specimens: complete cytogenetic response (CCyR) 0% Ph+ cells; partial (PCyR)1–35%; minor 39–65%; minimal 66–95%; none 96–100%. Iterative cytogenetic analyses were performed every 3 months during therapy. Toxicities were reported prospectively using the NIH CTCv2.0 criteria.Results. 50 children (42% boys), with a median age of 11.8 years (range 2.3–19.1) completed more than one course of therapy and were evaluable for response. Median number of courses delivered was 22.5 (range 1–43), with a median follow-up of 795 days. 96% of the calculated dose was administered. Eleven patients experienced 14 non-hematological grade 2–4 adverse events, and one patient discontinued therapy because of toxicity. The HR and CHR rates were 78% and 12%, at the end of course 1, and 20% and 78%, respectively, at the end of course 2. Only one patient was reported as a hematologic non-responder at the end of course 2. At the end of the third course, 33 patients were evaluated for cytogenetic response. Twelve (36%) children were in CCyR; 10 (30%) in PCyR; 5 in minor response; 4 in minimal response; 2 with no cytogenetic response. Six patients did not have cytogenetic evaluation; while in 11 (33%) the study was not possible due to insufficient sampling. Overall, 33 (66%) CCyRs were documented, at a median time of 5.6 months (91% documented by 9 months). Only 1 patient achieved a CCyR after course 10. Thirty-three children were removed from protocol, of which 23 underwent stem cell transplantation. One patient progressed to blast phase while on therapy, while six additional patients had cytogenetic progression. Of the 3 remaining patients, two patients had difficulty with taking medications and one had grade 4 liver toxicity. At 1 year, the estimated event free and overall survivals are 96% and 98%, respectively.Conclusion. Imatinib is well tolerated in previously untreated children with CP CML and induces comparable rates of complete cytogenetic response to those observed in adults. Current evaluation of molecular response is being performed.

Alternating intravenous and oral vinorelbine plus epirubicin with pegfilgrastim as neoadjuvant treatment of locally advanced breast cancer

In order to downstage locally advanced breast cancer, neoadjuvant chemotherapy consisting of intravenous vinorelbine 25 mg/m plus epirubicin 75 mg/m given on day 1 and oral vinorelbine 60 mg/m on day 8 was administered every 3 weeks for four courses. On day 2, all patients received a single subcutaneous injection of pegfilgrastim (6 mg). From March 2004 to June 2005, 22 patients were enrolled. Patients characteristics were: median age, 53 years (range: 39-70 years); postmenopausal, 7/22; clinical TNM stage, T2 (n=14), T3 (n=8), N0 (n=17) and N1 (n=5). The median number of courses was four (range: two to six courses) with full dose intensity. National Cancer Institute grade 3 haematological toxicities observed were neutropenia in 9% of patients, anaemia in 13% of patients and thrombocytopenia in 9% of patients; no toxicity grade 4 occurred. Two patients (9%) registered grade 2 polyneuropathy; no cardiac failure was observed. Conservative surgery was performed in 14 patients (63%). All patients were evaluable for response: complete pathological response was documented in three patients (13.6%); three patients (13.6%) obtained more than 75% of tumour size reduction; 11 other patients (50%) had 50% of tumour size reduction; stable disease was observed in five patients (22.7%). The present findings indicate that vinorelbine in combination with epirubicin is an effective and safe treatment in locally advanced breast cancer: this regimen obtained more than 50% of tumour size reduction in 77% of patients; the use of pegfilgrastim allowed full dose intensity. Oral vinorelbine on day 8 offers greater convenience to the patient by reducing the need for intravenous injection and the time spent in hospital.

Safety and efficacy of thalidomide in recurrent epithelial ovarian and peritoneal carcinoma

Objective. Thalidomide is an anti-angiogenesis agent that has shown activity in some solid tumors. We performed a phase I clinical trial to determine the toxicity and potential efficacy of Thalidomide in recurrent epithelial ovarian carcinoma. Methods. Patients with recurrent ovarian cancer were evaluated between 1998 and 2000. Data were evaluated using Kaplan–Meier and logistic regression analyses. Results. 17 heavily pretreated patients with recurrent epithelial ovarian cancer received oral Thalidomide starting at 100 mg/day, with dose escalations of 100 mg/day every 2 weeks, up to 1200 mg/day as tolerated. The median number of courses was four (range: 1–18 courses), and median dose was 200 mg/day (range: 100–600 mg/day). Treatment duration ranged from 2 to 48 months. Common grade 1 or 2 side effects included constipation (76%), neuropathy (71%), and fatigue (65%) with few grade 3 or 4 events. Three (18%) patients had partial responses, and six (35%) had stabilization of disease after 6 months. After 1 year of treatment, six of the nine patients with an initial partial response ( n = 2) or stable disease ( n = 4) remained in these response categories. Median time to progression was 10 months. Forty-seven percent of patients had a 50–70% decrease in CA125 levels. Using logistic regression and repeated measures analyses, CA125 levels decreased by 62 units/ml per month ( p = 0.07). Conclusion. Our study demonstrates the safety, tolerability, and potential efficacy of Thalidomide in recurrent and refractory epithelial ovarian cancers. Additional clinical trials are warranted.

Effect of oxaliplatin-capecitabine first-line chemotherapy and tumor response on serum proteomic profiles in advanced colorectal cancer and identification of diagnostic biomarkers

3603 Background: Colorectal cancer (CRC) is the third most common cause of cancer related death. Prognosis is highly dependent on stage at diagnosis making early diagnosis mandatory. Previously we identified serum biomarkers for CRC, by comparing serum from CRC patients and healthy controls, using SELDI-TOF mass spectrometry. Methods: We validated our identified biomarkers and assessed the effect of first-line oxaliplatin (130 mg/m2 day 1, q21)-capecitabine (1000 mg/m2 d1–14, q21) therapy by prospective standardized serum sampling at &lt; 2 weeks prior to start of chemotherapy and serially before each chemotherapy cycle in patients with advanced CRC. Samples were drawn according to standardized protocol, centrifuged within 1 hour and stored at -30°C. After thawing they were analyzed with SELDI-TOF MS on CM10 chips at pH 5. Healthy control subjects were matched according to age, gender and time of serum collection. For serial analysis the time points T: 0, 6, 12 and 18 - 24 weeks were used. All patients had given written consent, had WHO PS ≤ 2 and measurable disease, according to RECIST criteria, and/or were evaluable by CEA. Results: In total 42 patients (mean age: 57 years; range: 37 - 73; male 62%), were treated between 06/2003 and 09/2005. All patients were previously untreated except 8 patients who had received radiation or chemo-radiation for rectal carcinoma (all &gt; 6 months). Median follow up was 45 weeks and median number of courses was 5.5 (range: 1 -10). Response rate was 46%; PR in 19, SD in 12 and PD in 10 patients, respectively (1 not evaluable) and median overall survival was 10.5 months. We identified 6 peptides/proteins (m/z: 31948, 8078, 28101 (apolipoprotein A-I), 7970, 5912 and 12861 Da, respectively (in order of significance) discriminating between CRC and healthy controls (p &lt; 0.001). In a serial analysis of the patients a peptide, with m/z: 5.9-kDa (most likely fibrinogen split product) declined, during chemotherapy in some responsive patients, but apolipoprotein A-I appeared not to change. Conclusions: We confirmed our previous identification of apolipoprotein A-I (m/z: 28-kDa) as a potential biomarker for CRC and suggest a peptide with m/z: 5.9-kDa as a potential biomarker of response. No significant financial relationships to disclose.

A phase II of high dose capecitabine plus irinotecan for patients with advanced or metastatic gastric cancer: preliminary results

14086 Background: Capecitabine is the prodrug of 5-FU to generate maximal tumor activity in tumor site and/or improve the tolerability, has demonstrated the synergistic activity with irinotecan in some solid cancers . Previous study showed the dose intensification of capecitabine increased the response rate with comparable toxicities in metastatic colorectal cancer. We conducted this study to ascertain the efficacy and toxicity of irinotecan and high dose capecitabine combination chemotherapy for chemotherapy-naïve advanced or metastatic gastric cancer. Methods: Patients who were advanced or metastatic gastric cancer and have not received any chemotherapeutic drug except adjuvant chemotherapy, received irinotecan 130mg/m2 intravenously (i.v) for 90 min on day 1 and day 15 and capecitabine 3500 mg/day, divided two, was administered for 7 consecutive days from day1 and day 15, and this was followed by a 7-day drug-free interval. Results: 35 eligible patients were enrolled in this study from Nov/2003 to Nov/2006. 14 women and 21 men: median age 51 ys, range 27–81. A total 106 courses were administered, and median number of courses per patient was three (range, 1–8). Intent-to-treatment analysis showed the one complete response (2.9%), 13 partial responses (37.1%), 9 stable disease (25.7%), 8 progressive disease (22.9%) and 4 non-evaluable patients (11.4%). The overall response rate was 40% (95% CI: 23.5–56.5). Grade 3–4 toxicities were: neutropenia 8 (22.8%), nausea/vomiting 2 (5.7%), stomatitis 1 (2.9%), ischemic colitis 1 (2.9%), anemia 3 (8.6%), diarrhea 2 (5.7%), alopecia 3 (8.6%). Treatment related death was shown at one patient due to pneumonia. Dose intensity of irinotecan and capecitabine was 94% and 93%, respectively. Median time to progression was 4 months (range, 0.5 - 11 months), median survival duration was 8.5 months (range, 0.5 - 45 months), and median response duration was 2.5 months (range, 0.5 - 9 months). Conclusions: We suggest that irinotecan and high dose capecitabine combination chemotherapy is the tolerable regimen to advanced or metastastic gastric cancer with promising activity. No significant financial relationships to disclose.

Phase I trial involving the pharmacodynamic (PD) study of circulating tumour cells, of CP-751,871 (C), a monoclonal antibody against the insulin-like growth factor 1 receptor (IGF-1R), with docetaxel (D) in patients (p) with advanced cancer

3023 Background: C is the first specific, fully human, monoclonal antibody to target IGF-1R in clinical trials. It potently inhibits IGF-1R signaling, enhancing D antitumour activity. This trial investigated the safety, feasibility, dose limiting toxicity (DLT), PK and antitumor activity of D administered with C every 3 weeks. PD studies evaluated circulating tumor cell (CTC) IGF-1R expression and CTC counts pre- and post-treatment. Methods: The C doses tested were 0.1, 0.4, 0.8, 1.5, 3.0, 6.0 and 10 mg/kg in sequential cohorts of 3–6 p. D was fixed at 75mg/m2. P achieving disease control continued on C alone if experiencing D toxicity. Results: 21 p (20 male) have received 100 courses of C with D. 7 p received 8 or more courses of the combination. A further 21 courses of C alone have been administered. No toxicity has been attributed to C to date with the observed toxicities being attributable to D. Grade 3/4 toxicities were neutropenia (16/21 p) and neutropenic fever in 2/21 p. Grade 3 diarrhea was reported in 3 p, but this was easily controlled with antidiarrheals. Transient grade 1 hyperglycaemia was noted largely on day 1, following steroid premedication (14 p), but no significant C related hyperglycemia has been observed. An MTD has not been reached. Serial echocardiograms demonstrated no cardiac toxicity. Of 18 castration resistant prostate cancer (CRPC) p treated, 4 have had a confirmed PR, with 2 unconfirmed PR and 2 having disease stabilization for &gt; 6 months (median number of courses: 10; range: 3–12). 5 p have maintained SD with C alone for 2–7 courses. CTC were detected in 16 of 18 p (CTC numbers ranged from 1 to 202 in 7.5ml of blood). IGF-1R expression was detected in 12 p. CTC IGF-1R was undetectable following treatment with C at doses above 3 mg/kg. Conclusions: This combination is safe and feasible with no toxicity attributed to C and encouraging antitumor activity in CRPC. [Table: see text]

Phase II study of ‘hybrid‘ biochemotherapy for advanced melanoma

18007 Background: The clinical activity of a hybrid biochemotherapy regimen was determined. This regimen incorporated important elements of previously studied sequential and concurrent biochemotherapy regimens in order to potentially increase dose intensity of the antitumor agents while decreasing morbidity, complexity of in-patient management, and length of hospital days. Methods: The antitumor agents and starting doses in the hybrid regimen were: cisplatin (25 mg/m2) IV on days 2–5, vinblastine (1.4–1.6 mg/m2) IV on days 1–5, dacarbazine (800 mg/m2) IV day 1 only, rIL-2 (12 MIU/m2) SC on days 6–10, and interferon-a2b (10 MU/m2) SC on days 2–6. Thirty-seven patients (pts) with a median age of 49 (range 19–63) yrs and Zubrod’s PS of 0–2 were treated. Patients with prior chemotherapy, rIL-2, active brain metastases were excluded. All cycles were 21 days or longer and the median number of courses delivered per patient was 4 (range 1–6). Results: Thirty-five pts were evaluated for response. There were 3/35 (9%) complete responses (CRs) and 17/35 (49%) partial responses (PRs). One CR and one PR were confirmed pathologically. The median overall survival was 12.6 months (95% CI: 9.9, 20.3). The median time to progression for all patients was 5.7 months (95% CI: 4.3, 9.8), while the TTP of responders was 7.2 months (95% CI: 5.1, 18.9). Brain metastases developed in 13 pts, -either while receiving treatment and responding systemically (5 pts) -or post-treatment with progressive systemic disease (8 pts). There were 2/12 (17%) early deaths in pts receiving vinblastine (1.6 mg/m2), one with typhlitis and the other with sepsis. Therefore, the vinblastine dose was reduced to 1.4 mg/m2 for patients #13–35. Neutropenia, with a median lowest neutrophil count of 0.08 (range 0–3) on day 13 (range day 6–16), and fever during rIL-2 treatment, increased the median days of hospitalization of all patients to 15 (range 12–23) for the first cycle. Conclusions: Hybrid biochemotherapy produced a high response rate and an overall survival similar to previously reported schedules. Length of hospital stay was significantly increased compared to the concurrent schedule. Development of brain metastases in responding pts resulted in early withdrawal from the program. Hybrid biochemotherapy with reduced doses of vinblastine was better tolerated. No significant financial relationships to disclose.

Clinical activity and safety of the histone deacetylase inhibitor MGCD0103: Results of a phase I study in patients with leukemia or myelodysplastic syndromes (MDS)

6500 Background: MGCD0103 is a novel inhibitor of human histone deacetylases (HDACs), with selectivity for the cancer-associated isoforms of class I HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumour suppressor genes leading to neoplastic transformation, and therefore inhibition of this enzyme may result in antineoplastic activity. Methods: To study the safety and activity of MGCD0103, we have developed a phase I open-label dose escalation study of MGCD0103 administered orally, three-times weekly in patients with leukemia or MDS, with the primary endpoints being the determination of the maximum tolerated dose (MTD) and the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MGCD0103. Eligibility criteria included appropriate performance status and renal and hepatic functions. Patients with relapsed/refractory leukemia or MDS and older patients with untreated AML/MDS were eligible. Results: Twenty patients have been enrolled at four dose levels (20, 40, 80 and 60 mg/m2) so far. Their characteristics are: median age 60 years (range 33–76); the majority of patients so far treated have AML; median number of prior therapies is 1 (range 0–3). Most patients had complex cytogenetics. MGCD0103 has been well tolerated at doses below 80 mg/m2. The MTD has been reached, with 3 out of 4 patients at a dose of 80 mg/m2 developing grade 3 toxicity, mainly fatigue, nausea, vomiting or diarrhea. Grade 2 toxicities include anorexia, constipation, dehydration. The median number of courses is 1 (range 1 to 6). As of January 2006, 7 patients are on study. PK evaluations show dose-dependent exposure. Analysis of peripheral blood cell HDAC activity indicates that HDAC inhibition occurs in all patients in a dose-dependent manner. Two patients with multiple relapsed/refractory acute myelogenous leukemia, and one with MDS have achieved a complete marrow response (blasts less than 6%). Of importance, maximal HDAC inhibition was observed in those patients at the time of best response. Conclusions: Single-agent MGCD0103 has clinical activity and is well tolerated at doses below 80 mg/m2 orally three times a week in patients with advanced leukemia. No significant financial relationships to disclose.

A phase II study of S-1 in patients with hormone-refractory prostate cancer: The S-1 Cooperative Study Group (Prostate Cancer) study

14650 Background: S-1 is an oral fluoropyrimidine antitumor drug that combines three pharmacological agents: tegafur, a prodrug of 5-fluorouracil;gimeracil, an inhibitor of dihydropyrimidine dehydrogenase; and potassium oxonate, which reduces gastrointestinal toxicity. We evaluated the efficacy and safety of S-1 in patients with hormone-refractory prostate cancer. Methods: To be eligible patients (pts) had to have given informed consent, an age of &lt;80 years, elevations of serum prostate specific antigen (PSA) on three consecutive occasions despite effective hormonal therapy and antiandrogen withdrawal for at least 4 weeks, adequate organ function, a PS of 0–2, and a life expectancy of ≥3 months. S-1 was given orally at 40 mg/m2 b.i.d. for 28 consecutive days followed by a 14-day rest period. This 42-day cycle was repeated until confirmation of disease progression. Results: 32 pts were enrolled at 15 institutions. Their median age was 73 years (55 to 79). The median number of courses administered was 2.5 (1 to 11). On the basis of the change in the PSA level, 3 pts had a complete response (CR, &lt;4 ng/ml), and 4 had a partial response (PR, ≥50% decrease), yielding a response rate of 21%. There was no change (NC) in 15 pts, and progressive disease (PD) in 10 pts. The median time to PSA progression was 71 days (95% CI: 44 to 161) overall, 234 days (152 to 435+) in the CR+PR group, and 157 days in the CR+PR+NC group. Grade 3 major toxicity comprised anorexia (3 pts) and anemia (2 pts). No toxicity-related deaths occurred. Conclusions: S-1 is active and well tolerated as a single agent in patients with hormone-refractory prostate cancer. Effectiveness and safety will be confirmed in subsequent large-scale phase II studies. No significant financial relationships to disclose.

Pediatric phase 1 study of pemetrexed: A report from the Children’s Oncology Group

9019 Background: Pemetrexed is a new multi-targeted antifol that inhibits enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Methods: A phase 1 dose escalation and pharmacokinetic study (PK) was performed in children with refractory solid tumors to define the dose limiting toxicities (DLTs) and a recommended phase 2 dose. Pemetrexed was administered as a 10 min iv infusion every 21 days. All patients received folic acid (400 mcg/day po), vitamin B12 (500–1000 mcg every 3rd course IM) and dexamethasone (0.1 mg/kg/dose bid × 3 days each course) . Cohorts of 3 to 6 children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910 and 2,480 mg/m2. DLT was defined as any Gr. 3 or 4 non-hematological toxicity (except nausea/vomiting, alopecia, or AST/ALT elevation that returns to Gr. 1), Gr. 4 neutropenia or Gr. 4 thrombocytopenia ≥ 7 days. Results: 33 subjects (31 fully evaluable for toxicity), median age of 12 yrs (range, 1–21), with diagnoses including osteosarcoma (12), Ewing’s sarcoma (3), hepatoblastoma (2), renal cell carcinoma (2), brainstem glioma (3), glioma (3), and other (n=8) were enrolled. DLT occurred in 1/6 patients at 1,470 mg/m2 (Gr. 3 AST and ALT), and in 2/4 at 2,480 mg/m2 (Gr. 3 ANC and Gr. 3 rash in both). Other DLTs at 2,480 mg/m2 that occurred in 1 patient included Gr. 3 diarrhea and rectal hemorrhage, and Gr. 4 thrombocytopenia, lipase, GGT, hypophosphatemia, hypokalemia and hyponatremia. At 1,910 mg/m2, 0/6 patients had DLT. The median number of courses administered was 1 (range 1 to 17). No CRs or PRs have been observed. Results of PK and other correlative studies will be presented. Conclusions: The recommended phase 2 dose of pemetrexed for children and adolescents with recurrent solid tumors is 1,910 mg/m2 administered q21 days with dexamethasone, folic acid and B12 supplementation. A phase II COG study is planned. No significant financial relationships to disclose.

A phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) in advanced biliary tract carcinoma

BackgroundUnresectable biliary tract carcinoma is known to demonstrate a poor prognosis. We conducted a single arm phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) for advanced biliary tract malignancies basically on an outpatient basis.MethodsBetween February 1996 and September 2003, 42 patients were enrolled in this trial.LFP therapyBy using a total implanted CV-catheter system, 5-FU (160 mg/m2/day) was continuously infused over 24 hours for 7 consecutive days and CDDP (6 mg/m2/day) was infused for 30 minutes twice a week as one cycle. The administration schedule consisted of 4 cycles as one course. RESIST criteria (Response evaluation criteria for solid tumors) and NCI-CTC (National Cancer Institute-Common Toxicity Criteria) (ver.3.0) were used for evaluation of this therapy. The median survival time (MST) and median time to treatment failure (TTF) were calculated by the Kaplan-Meier method.ResultsPatients characteristics were: mean age 66.5(47–79): male 24 (54%): BDca (bile duct carcinoma) 27 GBca (Gallbladder carcinoma) 15: locally advanced 26, postoperative recurrence 16. The most common toxicity was anemia (26.2%). Neither any treatment related death nor grade 4 toxicity occurred. The median number of courses of LFP Therapy which patients could receive was two (1–14). All the patients are evaluable for effects with an over all response rates of 42.9% (95% confidence interval C.I.: 27.7–59.0) (0 CR, 18 PR, 13 NC, 11 PD). There was no significant difference regarding the anti tumor effects against both malignant neoplasms. Figure 2 Shows the BDca a longer MST and TTF than did GBca (234 vs 150, 117 vs 85, respectively), but neither difference was statistically significant.The estimated MST and median TTF were 225 and 107 days, respectively. The BDca had a longer MST and TTF than GBca (234 vs 150, 117 vs 85, respectively), but neither difference was statistically significant.ConclusionLFP therapy appears to be useful modality for the clinical management of advanced biliary tract malignancy.

Weekly paclitaxel as second-line chemotherapy for advanced or recurrent gastric cancer

Paclitaxel scheduled every 3 weeks has shown a response rate of approximately 20% for gastric cancer, with modest hematological toxicity. Weekly administration of paclitaxel in patients with breast or ovarian cancer has shown equivalent efficacy and milder toxicity compared with an every-3 week schedule. We investigated, retrospectively, the antitumor effects and toxicity profiles of weekly paclitaxel for patients with metastatic or recurrent gastric cancer in clinical practice. In 38 patients who had metastatic or recurrent histologically confirmed gastric cancer and a history of one prior chemotherapy regimen, other than paclitaxel or docetaxel, paclitaxel (8 mg/m2) was administered weekly, three times every 4 weeks, with short-term premedication. All 38 patients had had prior chemotherapy that included 5-fluorouracil, the fluoropyrimidine anticancer drug S-1, or cisplatin. The median number of courses in the present regimen was 6 (range, 1-44+). Dose intensity was 5mg/m2 per week, corresponding to 92% of the planned dose (6 mg/m2 per week). The overall response rate was 24% (6/25) in measurable lesions, and pleural effusion and ascites disappeared in 2 of 7 patients (29%) and in 3 of 21 patients (14%), respectively. Median survival time was 151 days from the commencement of this treatment, with a median follow-up period of 260 days. Grade 3 or 4 leukopenia and neutropenia were observed in 11 (29%) and 12 (32%) patients, respectively. Seven patients (18%) died within 30 days of the last administration of paclitaxel. Weekly paclitaxel seems to be active as second-line chemotherapy against metastatic and recurrent gastric cancer. Further study is needed to confirm the efficacy and safety of weekly paclitaxel.

Short-time infusion of oxaliplatin in combination with capecitabine (XELOX30) as second-line therapy in patients with advanced colorectal cancer after failure to irinotecan and 5-fluorouracil

Background: The efficacy of oxaliplatin combined with capecitabine (XELOX) as second-line therapy in patients with advanced colorectal cancer (ACRC) resistant to irinotecan is not well established. Oxaliplatin induces acute, cold-induced neuropathy in most patients. The incidence is claimed to be infusion rate-dependent and therefore a 2-h infusion is recommended.Patients and methods: For practical and economic reasons, but also for patient's convenience, we performed a phase II study to examine XELOX30 (capecitabine 1000mg/m2 orally twice daily on days 1–14 and oxaliplatin 130mg/m2 as a 30min infusion on day 1) in patients with ACRC resistant to irinotecan. In addition the pharmacokinetics of oxaliplatin was studied.Results: From November 2002 to September 2003, 70 patients with ACRC were treated with XELOX30. Median age was 62 (range 33–74 years) years and median performance status was 1 (range 0–2). The median number of courses was four (range 1–12) and median cumulative dose of oxaliplatin was 530 (range 125–1560 ) mg/m2. The response rate was 17% (95% CI 10–23), median time to progression (TTP) was 5.4 months (95% CI 4.6–6.4) and median survival 9.5 months (95% CI 8.5–11.2). White blood cell count (WBC) and performance status were significantly correlated to TTP. Neurotoxicity was moderate: grade 1 56%, grade 2 17% and grade 3 6%. Other grade 3 toxicities were nausea/vomiting 9%, diarrhoea 14% and PPE 8%. The maximum blood concentration and total body clearance of oxaliplatin was higher than previously reported in studies examining 2-h infusions, but the volume of distribution and terminal half-life was in close agreement with previous results.Conclusion: XELOX30 is a very convenient second-line regimen in ACRC with an activity and safety profile similar to other oxaliplatin schedules.